Tracking a TGF-β activator in vivo: sensitive PET imaging of αvβ8-integrin with the Ga-68-labeled cyclic RGD octapeptide trimer Ga-68-Triveoctin

• Published in: EJNMMI research Vol. 10; no. 1; pp. 133 - 12
• Main Authors: Quigley, Neil Gerard, Steiger, Katja, Richter, Frauke, Weichert, Wilko, Hoberück, Sebastian, Kotzerke, Jörg, Notni, Johannes
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 31.10.2020; Springer Nature B.V; SpringerOpen
• Subjects: Beta8; Blood; Cardiac Imaging; Chemical synthesis; Computed tomography; Gallium-68; Growth factors; Human subjects; Imaging; Integrins; Kidneys; Mapping; Medical imaging; Medicine; Medicine & Public Health; Muscles; Nuclear Medicine; Oncology; Organs; Original Research; Orthopedics; Positron emission; Positron emission tomography; Preclinical imaging; Radiochemistry; Radiology; Tomography; Transforming growth factor beta; Trimers; Tumors; Xenotransplantation; Beta8; Preclinical imaging; Gallium-68; Transforming growth factor beta; Positron emission tomography; Integrins
• ISSN: 2191-219X; 2191-219X
• DOI: 10.1186/s13550-020-00706-1

Purpose As a major activator of transforming growth factor β (TGF-β), the RGD receptor αvβ8-integrin is involved in pathogenic processes related to TGF-β dysregulation, such as tumor growth, invasion, and radiochemoresistance, metastasis and tumor cell stemness, as well as epithelial-mesenchymal transition. The novel positron emission tomography (PET) radiopharmaceutical Ga-68-Triveoctin for in vivo mapping of αvβ8-integrin expression might enhance the prognosis of certain tumor entities, as well as support and augment TGF-β-targeted therapeutic approaches. Methods Monomeric and trimeric conjugates of cyclo(GLRGDLp( N Me)K(pent-4-ynoic amide)) were synthesized by click chemistry (CuAAC), labeled with Ga-68, and evaluated in MeWo (human melanoma) xenografted SCID mice by means of PET and ex-vivo biodistribution. αvβ8-integrin expression in murine tissues was determined by β8-IHC. A human subject received a single injection of 173 MBq of Ga-68-Triveoctin and underwent 3 subsequent PET/CT scans at 25, 45, and 90 min p.i.. Results The trimer Ga-68-Triveoctin exhibits a 6.7-fold higher αvβ8-integrin affinity than the monomer (IC 50 of 5.7 vs. 38 nM, respectively). Accordingly, biodistribution showed a higher tumor uptake (1.9 vs. 1.0%IA/g, respectively) but a similar baseline upon blockade (0.25%IA/g for both). IHC showed an intermediate β8-expression in the tumor while most organs and tissues were found β8-negative. Low non-target tissue uptakes (< 0.4%IA/g) confirmed a low degree of unspecific binding. Due to its hydrophilicity (log D  = − 3.1), Ga-68-Triveoctin is excreted renally and shows favorable tumor/tissue ratios in mice (t/blood: 6.7; t/liver: 6.8; t/muscle: 29). A high kidney uptake in mice (kidney-to-blood and -to-muscle ratios of 126 and 505, respectively) is not reflected by human PET (corresponding values are 15 and 30, respectively), which furthermore showed notable uptakes in coeliac and choroid plexus (SUVmean 6.1 and 9.7, respectively, 90 min p.i.). Conclusion Ga-68-Triveoctin enables sensitive in-vivo imaging αvβ8-integrin expression in murine tumor xenografts. PET in a human subject confirmed a favorable biodistribution, underscoring the potential of Ga-68-Triveoctin for mapping of αvβ8-integrin expression in a clinical setting.